Philippova, Maria and Joshi, Manjunath B. and Pfaff, Dennis and Kyriakakis, Emmanouil and Maslova, Kseniya and Erne, Paul and Resink, Thérèse J.. (2012) T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells. Cardiovascular Research, Vol. 93, H. 3. pp. 498-507.
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Official URL: http://edoc.unibas.ch/dok/A6164877
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Abstract
T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes.; We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC.; T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRes.
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Signal Transduction (Resink/Erne) |
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UniBasel Contributors: | Resink, Thérèse J. and Erne, Paul |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Oxford University Press |
ISSN: | 0008-6363 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
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edoc DOI: | |
Last Modified: | 13 Mar 2018 17:18 |
Deposited On: | 25 Oct 2013 08:33 |
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